Method of treating proteic anabolism



United States Patent O 3,290,217 METHOD OF TREATING PROTEIC ANABOLISM Genevieve Azadian, Paris, France, assignor to Roussel- UCLAF, Paris, France, a corporation of France No Drawing. Filed Mar. 2, 1964, Ser. No. 348,755 Claims priority, application France, Mar. 5, 1963, 926,872 2 Claims. (Cl. 16774) The invention relates to novel compositions for the treatment of proteic anabolism which contain 17x-methyl- A -androstadiene-l7fl-ol as the active principle. The invention also relates to a novel method of treating prote-ic :anabolism.

Numerous anabolic agents are known such as 17amethyl-testosterone and 17a-methyld9 nor-ttestosterone which are active orally but they also possess .a pronounced androgenic activity.

It is an object of the invention to provide compositions for the treatment of proteic anabolism with little androgenic activity.

It is another object of the invention to provide a novel method of treating proteic anabolism.

These and other objects and advantages of the invention will become obvious from the following detailed description.

The novel compositions of the invention for the treatment of proteic anabolism are comprised of Hot-methyl- A -androstadiene-17 3ol of the formula I OH /A.

and a major amount of a pharmaceutical carrier. The said compositions may be in the form of injectable solutions or suspensions in ampules and multiple dose treatment of astheni, thinness, disturbances of growth and syrups and capsules prepared in the usual manner.

The compositions of the invention are useful for the treatment of asthenia, thinness, disturbances of growth and metabolic disturbances due to prolonged corticotherapy.

The method of the invention of treating proteic anaboli-sm comprises administering to warm blooded animals an effective amount of 17a-methyl-A -androstadiene-l75- 01. The said product can be administered orally, perlingually, transcuta-neously and rectally. The usual useful dosology is between 5 and 10 mg. per dose and 10 and 40 mg. per day in the adult depending upon the method of administration.

17ot-methyl-Mfiendrostadiene-l7,B-ol may be prepared by reacting 17a-methyl-A -andro-stene-3 l3,17,8-diol with a dehydrating agent such as sulfuric acid according to the following reaction scheme.

I on.

In the following examples there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

3,290,217 Patented Dec. 6, 1966 1.203 gm. of 17a-methyLA -androstene-3B,17fldiol were admixed with a solution of 60 cc. of ethyl alcohol, 30 cc. of water .and 15 cc. of N sulfuric acid and the mixture was heated to reflux for one hour with agitation to eifect rapid dissolution. Then, the reaction mixture was iced and the precipitate formed was separated by vacuum filtration, washed with water and dried to obtain 0.90 gm. of a product melting at 144-145 C. The said product was dissolved in 13.5 cc. of hot ethyl alcohol and the vresulting solution was filtered. 4 cc. of hot water were added thereto and the solution was slowly cooled. The crystals formed were separated, vacuum filtered, washed and dried to obtain 0.69 gm. of Hot-methyl- A -androst-adiened-01 having a melting point of 147- 148 C.

The product occurred in the form of a colorless solid soluble in benzene, chloroform and alcohol, slightly soluble in aqueous alcohol and insoluble in water.

Analysis.C H O; molecular weight=286.44. Calculated: C, 83.85%; H, 10.56%. Found: C, 83.40%; H, 10.50%.

U. V. Spectra (ethanol): x 228 m e=18,900; X 235 I11,u., e=20,500; 244 m e=13,l00.

Pelc (Coll. Czech. Chem. Comm., vol. 25, 1960, p. 309) has described a product allegedly having the formula of 17oc-methyl-A -androstadiene-l7,8-ol but the product shows different physical characteristics. Moreover, no medical study of the said product has been made.

Example II.-Preparation of injectable suspension of I 7u-methyl-A -androstadiene-I 7,8-01

17a-methyl-A -androstadiene-1713-01 was sterilized by heating it in suspension in an aqueous solution of benzyl alcohol and was then aseptically micropulverized in its liquid phase. To the resulting suspension, there were aseptically added an aqueous solution of sodium chloride whose concentration was 9 to 50 parts per thousand (to make the solution isotonic), polysorbate (a nonionic surface active agent) and an aqueous solution of sodium carboxymethyl cellulose whose concentration was 0.5 to 2.0 parts per hundred (viscosity agent) which substances had been previously stcrilized by heat. The said suspension was adjusted to a concentration of 1 gm. of product per cc. The suspension, maintained homogeneous by agitation, was aseptically divided and placed in ampules or flacons having a volume of 1 to 20 cc. Other injectable suspensions having concentration between 05 and 20 parts per hundred could be prepared by a similar procedure.

Example III.P/-eparati0n of tablets containing 5 mg. of 1 7 a-methyl-A -andr0stadiene-1 75-01 17a-methyl-A -androstadiene-17,8-01, white sugar, potato starch and lactose were successively introduced into an appropriate mixer and after the mixture was homogenized, an aqueous solution of gelatine was added in sufficient quantity to obtain a pretableting mass suitable for granulation on a perforated metallic plate. After granulation, the granules were spread as a thin layer on a platform and dried in an oven at 50 C. The dry granules were then ground through a metallic cloth of appropriate size and admixed with talc and magnesium stearate for lubrication. The granular powder was pressed into tablets of the desired weight and the average weight tolerance of a lot of 10 tablets was i5% of the theoretical weight. The weight of the tablets should be between 80 and 750 mg. for oral administration and should contain 0.6 to 6% of 17a-methyl-A androstadiene-1713-01.

Example I V.Preparatin of suppositories containing- 10 mg. of 17a-methyl-A -androstadiene-17,8-01' phenol was rinsed with a small amount of the cocoa butter which was added to the double jacketed cell. The first mixture containing the active product was then added thereto in small fractions and the mixture was then placed in a cell having as tight a lid as possible. A slight current of nitrogen was passed into the cell and a current of cold water was passed through the double jacket until The test consisted of administering daily oral doses of the products being tested in aqueous suspension to lots of male rats which had been castrated at the age of 3 /2 weeks. The rats were treated starting the day after castration for a period of 10 days with 1 to mg. of product per rat and per day and were then sacrificed on the eleventh day, 22 to 26 hours after the last administration. The sacrificed animals were autopsied and the necessary organs were separated and weighed. The lifter muscle of the anus (levator ani) was studied for the anabolic activity and the ventral prostate and the seminal vesicules were studied for the simultaneous androgenic effect. The results of the tests with 17a-methyl-A androstadiene-lm-ol and 17a-methyl-testosterone (for comparison) are summarized in the following table.

TAB LE Duration Body Weight in gm. Seminal Ventral Fresh Dried Treatment Daily of treatveslcules prostate Levator Li (1) Levator Ls (2) Dose ment (mg) (mg) ani ani (days) Initial Final (mg) (mg.)

Control 0 48 92 6 .6 16 .6 16 .94 0 .184 4 .1 0 .045 Hot-methyl testosterone 1 10 49 97 61.8 38 .4 0.395 12 .3 0 .124 5 10 46 83 (i1 .0 99 .0 31 .6 0 .377 7 .2 0.085 170t-methyl-A -androstadiene- 17fl-01 1 10 49 99 9 .8 35 .1 .9 0 .253 e .4 0 .0 4 5 10 49 87 18 .6 52 .9 39 .3 0 .450 9 0 .103

Ls=ratio of the weight of the dried levator ani 10 to the body weight.

the reaction mass had a pasty consistency or a temperature of about 25 C.

The said material was then reheated slightly by passing steam through the double jacket to bring the mass to a sufiiciently fluid consistency for casting (-32 C.). This temperature and mechanical stirring were maintained during casting. The reaction mass was poured through a lateral orifice heated to into a series of small cells held by metallic bands. After several minutes, the reaction mass solidified and the cells were levelled with a wiper. The assembly of cells was placed in a refrigerated chest maintained at 10 C. to effect solidification of the suppositories. The metal bands were removed from the cells in the refrigerated chest and the cells were opened to obtain 10 suppositories having a final weight of 2 gm. and containing 10 mg. of 17amethyl-A -androstadiene-17B-ol.

Pharmacological data.Androgenic and anabolic activity determination The test was effected according to the method of Hershberger (Proc. Soc. Exp. Biol. Med., vol. 83, 1953, p. 175) slightly modi ed.

The above table shows that 17u-methyl-A -androstadiene-17fi-ol possess an anabolic activity comparable to l7oc-methyl-testosterone but has a weaker androgenic activity.

Various modifications of the compositions of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only as defined in the appended claims.

I claim:

1. A method of treating proteic anabolism in warm blooded animals which comprises administering daily an effective amount of 17 a-methyl-A -androstadiene-17,8-01.

2. The method of claim 1 wherein the elfective amount is 10 to 40 mg.

References Cited by the Examiner Pelc: Collection Czechoslovak Chemical Communications, vol. 25, pp. 309-312.

JULIAN S. LEVITT, Primary Examiner.

L. B. RANDALL, Assistant Examiner. 

1. A METHOD OF TREATING PROTEIC ANABOLISM IN WARM BLOODED ANIMALS WHICH COMPRISES ADMINISTERING DAILY AN EFFECTIVE AMOUNT OF 17A-METHYL-$3,5-ANDROSTADIENE-17B-OL. 